This application will test the hypothesis that SP-A play a critical role in lung function during adenoviral mediated lung injury by modulated 1) host defense, 2) inflammatory responses, and 3) surfactant homeostasis, by interacting with surface receptors on respiratory epithelial cells and alveolar macrophages. We propose that SP-A serves complex regulatory roles in the lung, binding to cell surface receptors present on Type II cells and alveolar macrophages, influencing 1) binding, uptake and killing of microorganisms and 2) inflammatory responses of epithelial cells and alveolar macrophages to microorganisms. The application will utilize models in which the synthesis of SP-A is altered genetically, using SP-A/-, SP-A+/+ mice or by intratracheal instillation of purified mouse SP-A. SP-A will be replaced genetically, in distinct subsets of respiratory epithelial cells. SP-A deficient and replete mice will be exposed to adenovirus to determine the role of P-A in lung inflammation and function. The studies will discern the concentration dependent and region-specific role of SP-A in innate defense and in surfactant homeostasis in the lung. We will determine the molecular mechanisms controlling SP-A gene transcription in the normal lung and after adenoviral induced inflammation. The role of SP-A in the modulation of respiratory epithelial cells and alveolar macrophage responses to a pro- inflammatory stimulus induced by adenovirus will be assessed. We propose that SO-A interacts in complex ways with multiple receptors n target cells, including epithelial cells and alveolar macrophages. We will identify, clone and assess binding specificity of the SP-A/Clq receptor/binding protein that is proposed to mediate, at least in part, SPA-function. These studies will help clarify the role of SP-A in innate defense of the lung and provide the basis for future therapies to maintain endogenous or supply exogenous SP-A to prevent morbidity or bacterial infection.